Tropomodulin1 is required in the heart but not the yolk sac for mouse embryonic development.
Tropomodulin (Tmod)1 caps the pointed ends of actin filaments in sarcomeres of striated muscle myofibrils and in the erythrocyte membrane skeleton. Targeted deletion of mouse Tmod1 leads to defects in cardiac development, fragility of primitive erythroid cells, and an absence of yolk sac vasculogenesis, followed by embryonic lethality at embryonic day 9.5. The Tmod1-null embryonic hearts do not undergo looping morphogenesis and the cardiomyocytes fail to assemble striated myofibrils with regulated F-actin lengths. To test whether embryonic lethality of Tmod1 nulls results from defects in cardiac myofibrillogenesis and development or from erythroid cell fragility and subsequent defects in yolk sac vasculogenesis, we expressed Tmod1 specifically in the myocardium of the Tmod1-null mice under the control of the alpha-myosin heavy chain promoter Tg(alphaMHC-Tmod1). In contrast to Tmod1-null embryos, which fail to undergo cardiac looping and have defective yolk sac vasculogenesis, both cardiac and yolk sac morphology of Tmod1(-/-Tg(alphaMHC-Tmod1)) embryos are normal at embryonic day 9.5. Tmod1(-/-Tg(alphaMHC-Tmod1)) embryos develop into viable and fertile mice, indicating that expression of Tmod1 in the heart is sufficient to rescue the Tmod1-null embryonic defects. Thus, although loss of Tmod1 results in myriad defects and embryonic lethality, the Tmod1(-/-) primary defect is in the myocardium. Moreover, Tmod1 is not required in erythrocytes for viability, nor do the Tmod1(-/-) fragile primitive erythroid cells affect cardiac development, yolk sac vasculogenesis, or viability in the mouse.
McKeown
Caroline R
CR
The Scripps Research Institute, Department of Cell Biology, La Jolla, CA 92037, USA.
Nowak
Roberta B
RB
Moyer
Jeannette
J
Sussman
Mark A
MA
Fowler
Velia M
VM
D000199:Actins / Q000502:physiology; D000818:Animals; D047108:Embryonic Development; D005260:Female; D005318:Fetal Heart / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000502:physiology*; D008098:Litter Size; D008285:Major Histocompatibility Complex; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009210:Myofibrils / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012518:Sarcomeres / Q000502:physiology; D051348:Tropomodulin / Q000172:deficiency* / Q000235:genetics*; D015017:Yolk Sac / Q000502:physiology
D000199:Actins; C495831:Tmod1 protein, mouse; D051348:Tropomodulin; D018995:Myosin Heavy Chains